Objectives This study analyzed studies of mortality and survival impact of AVR in patients with low-gradient (LG) AS and preserved left ventricular ejection fraction, including paradoxical low-flow (i.e., stroke volume index <35 ml/m2), low-gradient (LF-LG) and normal-flow, low-gradient (NF-LG), and those with high-gradient (≥40 mm Hg) AS or moderate AS.

Methods Studies published between 2005 and 2015 were analyzed. Primary outcome was the survival benefit associated with AVR. Secondary outcome was overall mortality regardless of treatment.

Results Eighteen studies were included in the analysis. Patients with LF-LG AS have increased mortality compared with patients with moderate AS (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.31 to 2.17), NF-LG (HR: 1.80; 95% CI: 1.29 to 2.51), and high-gradient (HR: 1.67; 95% CI: 1.16 to 2.39) AS. AVR was associated with reduced mortality in patients with LF-LG (HR: 0.44; 95% CI: 0.25 to 0.77). Similar benefit occurred with AVR in patients with NF-LG (HR: 0.48; 95% CI: 0.28 to 0.83). Compared with patients with high-gradient AS, those with LF-LG were less likely to be referred to AVR (odds ratio: 0.32; 95% CI: 0.21 to 0.49).

Conclusions Patients with paradoxical LF-LG AS and NF-LG AS have increased risk of mortality compared with other subtypes of AS with preserved left ventricular ejection fraction, and improved outcome with AVR.

However, clinicians are sometimes confronted with patients with discordant findings, the most frequent being the combination of a measured small AVA (<1.0 cm2) consistent with the presence of severe AS but a low mean gradient (<40 mm Hg) rather indicating the presence of moderate AS (MAS). This low-gradient (LG) AS entity may raise uncertainty regarding the actual severity of the stenosis and the potential indication for AVR if the patient is symptomatic. This entity is often related to the presence of low LV outflow. Indeed, given that the pressure gradient is directly related to the squared function of transvalvular flow rate, even a modest decrease in flow rate can lead to an important reduction in gradient and thus to an underestimation of stenosis severity. This low-flow, LG (LF-LG) condition may occur in the context of either a reduced (i.e., classical LF) or preserved (i.e., paradoxical LF) LVEF. However, such discordance may also be observed in patients with normal LVEF and flow, in which case it may be caused by measurement errors, a small body size, or previously emphasized inherent inconsistencies in the guidelines AVA/gradient criteria (3).

According to current guidelines, AVR is recommended in: 1) symptomatic patients with high-gradient (HG) AS, regardless of their AVA, LVEF, or flow (Class I); 2) patients with classical (low LVEF) LF-LG after confirmation of stenosis severity by dobutamine stress echocardiography (Class IIa); or 3) symptomatic patients with paradoxical (preserved LVEF) LF-LG after confirmation of stenosis severity (Class IIa). The paradoxical LF-LG AS was described for the first time in 2007 (4) and the IIa recommendation for AVR in these patients was added in the 2012/2014 edition of the guidelines (2,5). The studies published before and after the publication of these guidelines have, however, yielded conflicting results with regard to the outcome and benefit of AVR in the patients with paradoxical LF-LG AS (6–11). Furthermore, the guidelines provide no specific recommendation for the symptomatic patients with preserved LVEF and normal-flow, LG (NF-LG) AS, although recent studies (12) suggest that an important proportion of these patients have severe AS.

The objective of this meta-analysis was thus to compare patients with LG AS and preserved LVEF, including paradoxical LF-LG and NF-LG, with those with HG AS or MAS with respect to overall mortality and impact of AVR on survival.

Methods

A literature search was performed in PubMed, Embase, Ovid, and Google Scholar for studies published between 2005 and 2015 without language restriction according to the following criteria: “low gradient aortic stenosis” OR “paradoxical low flow low gradient aortic stenosis.” The related articles function was used to broaden the search. The Cochrane library was also searched using the previously mentioned terms. All the review articles whose subject was LG AS and their reference lists were also reviewed.

Inclusion and exclusion criteria

Articles were included in the meta-analysis if they included any of the following:

2. Observational comparison of AVR (either surgical aortic valve replacement [SAVR] or transcatheter aortic valve replacement [TAVR]) versus conservative management in patients with LG, LF-LG, or NF-LG AS. When the studies included in this meta-analysis reported outcome data of patients with HG AS according to treatment, AVR versus conservative management, these results were included and analyzed.

The following exclusion criteria were used to select the final articles for the meta-analysis: <20 patients in any group, and use of other criteria other than recommended by the American College of Cardiology/American Heart Association and European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines (2,5) for the definition of severe and/or LG AS.

The study sites and inclusion were compared to ensure minimal patient overlap in different publications from the same site. If extensive overlap existed, only the publication with the largest or diagnostically most complete cohort (e.g., all patients instead of only patients with AS) was included. In case studies in which the outcome of AVR versus conservative treatment of patients with LG AS is analyzed separately from that of patients with LF-LG, both analyses were included and considered as different studies for the pooled analysis. LF (data for LF-LG) was added after the name of the author in the forest plots.

Outcomes

Primary outcome was the survival benefit associated with AVR in patients with LG, LF-LG, or NF-LG. The secondary outcome was the comparison of overall mortality, regardless of type of treatment, in patients with LF-LG, NF-LG, HG, and MAS. Data were obtained from unmatched populations in the included studies to get the real-life mortality risk of the patients with the different AS entities. The following variables were obtained to evaluate the surgical and cardiovascular risk of each group: prevalence of female patients, age, coronary artery disease, hypertension, diabetes, and renal failure.

Statistical analysis

For each individual study, hazard ratios (HRs) reflecting long-term mortality along with their corresponding variances were calculated. When only the survival curves were available, these were inspected and the overall mortality rates were estimated using 6-month intervals using the method of Parmar et al. (13). Overall log HRs using inverse variances as weights were then calculated for each study. The odds ratio was used as the summary statistic for categorical variables. For continuous variables, the summary statistic chosen was the mean difference.

Because of patient and treatment procedure heterogeneity in the included studies, random effects model was used to calculate the summary statistics and their 95% confidence intervals (CIs). Meta-analyses results are displayed in forest plots. Analysis was conducted using Review Manager Version 5.2 (The Cochrane Collaboration, Update Software, Oxford, United Kingdom).

Results

The search yielded 177 potential studies for analysis. Of these, 74 articles did not compare outcomes among groups as specified in the inclusion criteria, 34 articles were reviews or editorials, and 51 of them did not address specifically the topic of investigation or did not report the data required to analyze the primary or secondary outcomes of the present study. The final total number of studies included in the meta-analysis was 18 and the total number of patients was 7,459 (Table 1, Figure 1). None of these studies, except that of Herrmann et al. (14), which was a post-hoc analysis of the PARTNER-I (Placement of Aortic Transcatheter Valves I) trial, contained a randomized comparison of AVR versus conservative treatment. These articles comprised a total of 1,012 patients with MAS (59% were symptomatic, 35% underwent AVR), 3,056 patients with HG (75% symptomatic, 70% AVR), and 3,391 patients with LG AS (56% symptomatic, 58% AVR). Of the latter subset, 1,353 patients had LF-LG, 1,553 patients had NF-LG, and 581 patients had no definition of the flow status (LF vs. NF). Not all of the included articles reported both the primary and secondary outcomes specified previously (Figure 1).

Overall mortality

Patients with LF-LG AS have increased global risk of death compared with patients with MAS (HR: 1.68; 95% CI: 1.31 to 2.17) and those with NF-LG (HR: 1.80; 95% CI: 1.29 to 2.51) (Figure 2). The LF-LG patients also had higher risk of mortality compared with those with HG AS (HR: 1.67; 95% CI: 1.16 to 2.39). When patients with HG are compared with those with NF-LG, no differences were found with regard to mortality (HR: 1.12; 95% CI: 0.89 to 1.42).

Only 2 of the included studies reported outcome data in HG AS versus MAS. As expected, both studies found that HG AS is associated with increased risk of mortality compared with MAS (Clavel et al. [6]: HR: 5.82; 95% CI: 3.92 to 8.64; Tribouilloy et al. [11]: HR: 1.74; 95% CI: 1.27 to 2.39).

Survival benefit with AVR

In patients with LF-LG who undergo AVR, mortality was reduced by 56% (HR: 0.44; 95% CI: 0.25 to 0.77) (Figure 3). Similar survival benefit was obtained after AVR in patients with NF-LG (HR: 0.48; 95% CI: 0.28 to 0.83). When we included all studies that reported survival in LG AS irrespective of flow, patients who underwent AVR had reduced risk of overall mortality (HR: 0.44; 95% CI: 0.33 to 0.58). Patients with HG AS displayed the greatest survival benefit with AVR (HR: 0.25; 95% CI: 0.19 to 0.35). Compared with patients with HG AS, those with LF-LG were less likely to be referred to AVR (odds ratio: 0.32; 95% CI: 0.21 to 0.49) (Figure 4). Only 2 studies (6,11) reported data of AVR versus conservative management in patients with MAS and these 2 studies did not find any significant benefit of AVR on survival in these patients (Clavel et al. [6]: HR: 0.44; 95% CI: 0.17 to 1.12; and Tribouilloy et al. [11]: HR: 0.66; 95% CI: 0.36 to 1.22).

Comparison of patient baseline characteristics

Compared with patients with HG, those with LF-LG and those with NF-LG AS were older and had higher prevalence of coronary artery disease, diabetes, and hypertension (Online Figures S1 to S4). Patients with LF-LG had similar baseline characteristics compared with patients NF-LG (Online Figures S5 and S6).

Among patients with LF-LG AS, those who underwent AVR were older, were predominantly men, and had higher prevalence of renal failure (Online Figures S7 and S8).

Discussion

The main findings of this meta-analysis are: 1) patients with LF-LG AS have higher risk of overall mortality compared with those with MAS, NF-LG AS, and HG AS; 2) patients with NF-LG AS have higher risk of mortality compared with patients with MAS but similar risk compared with patients with HG AS; and 3) SAVR/TAVR improves overall survival in patients with LF-LG and in those with NF-LG AS (Central Illustration).

Outcomes and impact of AVR in paradoxical LF-LG AS

A relatively large proportion (30% to 50%) of AS patients with preserved LVEF have LF (stroke volume index <35 ml/m2) and because of the LF state, these patients often have a LG despite the presence of severe stenosis. The high prevalence of LF in the AS population is not necessarily surprising given that this population is predominantly elderly, with frequent comorbidities (systemic hypertension, coronary artery disease, diabetes, atrial fibrillation, mitral regurgitation, tricuspid regurgitation, mitral stenosis) and associated complications (pronounced LV concentric remodeling, impaired LV diastolic filling, ventricular dyssynchrony, impaired LV systolic longitudinal function). These comorbidities and associated complications may all contribute to reduce stroke volume and increase risk of mortality and morbidity. Accordingly, in most previous studies (4,6,8,15–22), patients with paradoxical LF-LG AS had worse symptomatic status and prognosis compared with those with MAS, NF-LG, or HG AS. However, some studies (10,11,23) found similar prognoses for LF-LG patients versus those with MAS, NF-LG, or HG AS.

LF-LG AS is a highly heterogeneous entity and the discrepancies between previous studies may be related to differences in the baseline characteristics of the study populations and in the Doppler-echocardiographic methods and definitions used to identify LF-LG AS (4,6–8,10,21,23–25). These factors may also explain why the prevalence of LF-LG AS varies extensively from one study to the other (5% to 35%) (3,4,10,11,16,20,21,26).

With low transvalvular flow, the forces applied against the valve cusps may not be sufficient to completely open a valve that is mildly or moderately stenotic. This “pseudosevere” AS phenomenon may occur with both classical and paradoxical LF-LG. Previous studies report that 30% to 50% of patients with paradoxical LF-LG AS have pseudosevere AS (12,27,28). Hence, discrepancies among previous studies with regard to the outcomes and survival benefit of AVR in patients with paradoxical LF-LG may also be, at least in part, related to differences in the proportion of patients with pseudosevere versus true severe AS included in each study. Nonetheless, the pooled analysis of the present study confirms that overall, paradoxical LF-LG AS is associated with increased risk of mortality compared with the other subtypes of AS with preserved LVEF. These findings also emphasize the importance of confirming the presence of severe stenosis before considering AVR in these patients, as recommended in the guidelines (2,5). Assessment of the morphological changes of the aortic valve (i.e., calcification, thickening) by transthoracic or transesophageal echocardiography, low-dose dobutamine stress echocardiography, or quantitative aortic valve calcium scoring by multidetector computed tomography may be used for this purpose (12,27,29).

The present study confirms that AVR is associated with a major survival benefit in patients with paradoxical LF-LG AS. Few studies (10,11,23) did not find a significant benefit of AVR, but most of these studies were underpowered for this specific analysis. The present study also confirms that patients with LF-LG are less often referred to AVR compared with those with HG AS. The presence of LG may result in underestimation of the stenosis severity and thus in underuse of AVR in patients with paradoxical LF-LG AS. This may have contributed to the increased risk of mortality observed in this subset.

Hence, the results of the present study provide further support to the Class IIa recommendation for AVR in symptomatic patients with paradoxical LF-LG severe AS.

Outcomes and impact of AVR in NF-LG AS

Although patients with NF-LG AS represent an important proportion (25% to 50%) of the AS population with preserved LVEF (3,7,8,11,21,30), the guidelines do not address the situation of these patients. As with LF-LG, NF-LG AS is also a highly heterogeneous entity that includes: 1) patients with errors in the measurement of the stroke volume, AVA, and/or gradient; 2) patients with small body size; and 3) patients with inconsistent grading. The latter category likely represents the largest proportion of the patients with NF-LG AS. From a fluid mechanics standpoint and if LV flow is normal, the cutpoint value of AVA of 1.0 cm2 proposed in the guidelines to define severe AS indeed corresponds more precisely to a mean gradient around 30 to 35 mm Hg rather than to the 40 mm Hg cutpoint given in the guidelines (3). Hence, patients with NF-LG AS are generally in the moderate-to-severe stenosis range and, accordingly, recent studies (12) reported that about 50% of these patients may have hemodynamically severe stenosis. There are no data about the natural history of NF-LG AS. However, it is possible that some patients with NF-LG AS may progress to HG AS, whereas others may evolve to LF-LG AS.

The present meta-analysis reveals that the outcome of the patients with NF-LG AS is similar to that of patients with HG AS and better compared with patients with LF-LG AS. Furthermore, AVR was associated with improved survival in patients with NF-LG. Hence, in light of these results, confirmation of stenosis severity with additional diagnostic tests should probably be considered in patients with NF-LG AS who are symptomatic.

Study limitations

We did not use individual data, therefore results and conclusions drawn from metaregression analysis regarding independent predictors should be interpreted cautiously. In the context of a meta-analysis, it is generally not possible to obtain individual data. It is therefore impossible to adjust the analyses of outcomes for potential confounding variables. In particular, it was not possible to assess the impact of symptomatic status on outcomes and benefit of AVR in the different subtypes of AS.

Observational comparisons of AVR with conservative treatment were nonrandomized and therefore subject to confounding by indication bias. In particular, some patients with severe AS and severe comorbidities may have been considered at too high risk for AVR and therefore left on conservative management. This bias may thus have overestimated the benefit of AVR.

Conclusions

Patients with paradoxical LF-LG AS have increased risk of mortality compared with all other subtypes of severe AS with preserved LVEF, and their outcome is improved by AVR. These findings support the guidelines recommendation (Class IIa) for AVR in these patients when they are symptomatic and when severe stenosis is the most likely cause of symptoms. Furthermore, patients with NF-LG also had similar risk of mortality compared with those with HG AS and their outcome was improved by AVR. These findings suggest symptomatic patients with NF-LG should also receive particular attention and that additional diagnostic tests should be considered in these patients to corroborate the stenosis severity and determine the indication for AVR.

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: AVR improves survival in patients with paradoxical low-flow, low-gradient and in those with normal-flow, low-gradient severe AS.

TRANSLATIONAL OUTLOOK: Further studies are needed to understand the pathophysiological mechanisms responsible for low-gradient severe AS and derive improved methods for clinical risk stratification for patients with this condition.

Appendix

Appendix

For supplemental figures, please see the online version of this article.

Footnotes

Dr. Pibarot holds the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research, Ottawa, Canada. The research program of Dr. Pibarot is funded by research grants (FDN-143225, MOP-126072, MOP-114997) from Canadian Institutes of Health Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

References

(2006) ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol48:598–675.

(2012) Guidelines on the management of valvular heart disease (version 2012). Joint task force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J33:2451–2496.

(2014) 2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol63:2438–2488.

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